There is a constant need for methods for the safe and effective administration of physiologically active agents. For many medications it is important that the administration regime is as simple and non-invasive as possible in order to maintain a high level of compliance by a patient. Oral administration is one administration regime that is commonly used because it is a relatively simple regime to follow. However, the oral administration route is also complicated because of complications associated with gastrointestinal irritation and with drug metabolism in the liver.
Administration of physiologically active agents through the skin (‘transdermal drug delivery’) has received increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation. However, transdermal drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism.
Structurally, the skin consists of two principle parts, a relatively thin outermost layer (the ‘epidermis’) and a thicker inner region (the ‘dermis’). The outermost layer of the epidermis (the ‘stratum corneum’) consists of flattened dead cells which are filled with keratin. The region between the flattened dead cells of the stratum corneum is filled with lipids which form lamellar phases that are responsible for the natural barrier properties of the skin.
For effective transdermal delivery of a physiologically active agent that is applied to the surface of the skin (‘topical application’), the agent must be partitioned firstly from the vehicle into the stratum corneum, it must typically then be diffused within the stratum corneum before being partitioned from the stratum corneum to the viable epidermis, dermis and into the bloodstream.
To overcome some of the problems with transdermal delivery that are associated with transport across the dermal layers (‘percutaneous absorption’), physiologically active agents can be formulated with incorporation of one or more drug penetration enhancers. For example, aqueous ethanol can be used as a vehicle in formulations for topical application. Ethanol can act as a penetration enhancer that can increase the flux of an active agent across the skin due to a solvent drag effect (Berner et al., 1989, J. Pharm. Sci, 78(5), 402-406). Padimate O, Octyl salicylate (U.S. Pat. No. 6,299,900) and Azone™ are further examples of penetration enhancers that have been shown to improve percutaneous absorption.
Compositions that form in-situ have previously found use as biodegradable in situ forming film dressings (U.S. Pat. No. 5,792,469) for the formation of barrier surfaces for open dermal wounds.
However to date the use of amorphous compositions for advanced drug delivery systems has been largely restricted to solid-state drug delivery systems such as; oral capsules an example of which is an amorphous paroxetine composition disclosed in WO 99/16440; or drug-in-adhesive, hot-melt type transdermal patches such as those disclosed in U.S. Pat. No. 5,662,923, U.S. Pat. No. 4,409,206, U.S. Pat. No. 6,264,980 and WO 95/18603. These existing amorphous delivery systems suffer from the particular disadvantage of being prone to poor stability during storage over their shelf-life which makes them particularly difficult to design and develop and in many instances has led to variability in drug release and/or dramatic changes in physical appearance (e.g. crystallization and supersaturation in drug-in-adhesive transdermal patch delivery systems). Other workers have also described the use of a transdermal spray composition that uses a film-forming composition to form a drug reservoir above the skin (U.S. Pat. No. 6,010,716) and such systems are akin to drug-in-adhesive patches that form in-situ.
Consequently there exists a need to develop new amorphous drug delivery systems with improved design and stability whilst building upon the advantages of an amorphous pharmaceutical composition.
Whilst it is feasible that transient formation of an amorphous pharmaceutical composition could occur from existing alcohol-based volatile:non-volatile vehicles such as those disclosed in a dual-phase carrier system that uses benzyl alcohol as the dermal penetration enhancer (U.S. Pat. No. 4,820,724), or those acetone-based volatile: non-volatile vehicles using DMSO, DMAC as penetration enhancers (Feldmann, R. J.; Maibach, H. I. Percutaneous penetration of 14C hydrocortisone in man. II. Effect of certain bases and pre-treatments. Arch. Derm. 1966, 94, 649-651). These existing volatile:non-volatile delivery systems suffer from the limitations of using water soluble dermal penetration enhancers that have poor substantivity for the skin and thus are unreliable in maintaining a stable amorphous composition within the skin over the delivery period due to their propensity to wash out of the skin. Further, these prior art systems are prone to irritate the skin due to the solvent nature of the penetration enhancers used within such prior art systems (which results in significant penetration of the enhancer into the viable epidermis).
Other methods of thermodynamic-based enhancement for improving percutaneous absorption have relied upon:                supersaturation (Coldman, M. F.; Poulsen, B. J.; Higuchi, T. Enhancement of percutaneous absorption by the use of volatile:nonvolatile systems as vehicles. J. Pharm. Sci. 1969, 58, 1098-1102); or        melting point reduction of the diffusant using deliberate selection of specific enantiomers (U.S. Pat. No. 5,114,946); or        melting point reduction using deliberate selection of eutetic mixtures (Touitou E., Chow, D. D., Lawter, J. R. Chiral β-blockers for transdermal delivery. Int. J. Phamm. 1994, 104, 19-28; Kaplun-Frischoff, Y; Touitou, E. Testosterone skin permeation enhancement by menthol through formation of eutectic with drug and interaction with skin lipids. J. Pharm. Sci. 1997, 86, 1394-1399.; Stott, P. W., Williams, A. C., Barry, B. W. Mechanistic study into the enhanced transdermal permeation of a model β-blocker, propranolol, by fatty acids: a melting point depression effect. Int. J. Pharm. 2001, 219, 161-176.).        
While these methods have all aimed at improvements in percutaneous absorption none have solved the problem of forming a stable amorphous composition capable of controlling the extent and/or profile of transdermal release of a physiologically active agent from within the skin whilst avoiding the skin irritation seen with prior art systems and compositions.
Further the benefits of a stable, in-situ forming amorphous pharmaceutical composition for release rate control within the skin are not foreseen by existing delivery systems which rely upon the control of release rate through the modification of the drug reservoir that resides above the skin such as that described for transdermal matrices that reside above the skin of the host and which are directed at deliberately modifying the profile of the transdermal drug delivery, such examples being described in U.S. Pat. No. 5,091,186 titled Biphasic transdermal drug delivery device, or U.S. Pat. No. 5,613,958, titled Transdermal delivery systems for the modulated administration of drugs or WO 93/00058, titled Solubility parameter based drug delivery system and methods for altering drug saturation concentration.
No admission is made that any reference, including any patent or patent document, cited in this specification constitutes prior art. In particular, it will be understood that, unless otherwise stated, reference to any document herein does not constitute an admission that any of these documents forms part of the common general knowledge in the art in Australia or in any other country. The discussion of the references states what their authors assert, and the applicant reserves the right to challenge the accuracy and pertinency of any of the documents cited herein.